Compressed high density fibrous polymers suitable for implant

ABSTRACT

An embodiment of the present invention may be made by the following steps: providing a mixture comprising a plurality of fibers, a lubricant, and a suspension fluid, with the suspension fluid filling a void space between said fibers and subjecting said mixture to at least one compressive force. The compressive force causes the migration and alignment of said fibers; and may remove substantially all of the suspension fluid from said mixture. The mixture may further comprise a biologically active agent, or a reinforcing agent.

RELATED APPLICATION

This application is a Divisional of U.S. patent application Ser. No.10/729,146, filed on Dec. 4, 2003, entitled COMPRESSED HIGH DENSITYFIBROUS POLYMERS SUITABLE FOR IMPLANT, which issued on Mar. 13, 2012 asU.S. Pat. No. 8,133,500, which is assigned to the same assignee as thisinvention, and whose disclosure is incorporated by reference herein.

BACKGROUND OF THE INVENTION

Despite the growing sophistication of medical technology, repairing andreplacing damaged tissues remains a costly, and serious problem inhealth care. Currently, implantable prostheses for repairing tissues aremade from a wide number of synthetic and natural materials. Ideally,these prosthetic material should be chemically inert, biocompatible,noncarcinogenic, capable of being secured at the desired site, suitablystrong to resist mechanical stress, capable of being fabricated in largequantities in the form required, sterilizable, and free of viruses orother contaminating agents. Examples of tissue that can be treated withimplantable prostheses include dura mater, tendon (e.g., rotator cuff,anterior cruciate, etc.) and rectic abdominus muscle due to herniation.

A wide variety of prosthetic materials have been used, includingtantalum, stainless steel, Dacron, nylon, polypropylene (e.g., Marlex),microporous expanded-polytetrafluoroethylene (e.g., Gore-Tex), dacronreinforced silicone rubber (e.g., Silastic), polyglactin 910 (e.g.,Vicryl), polyester (e.g., Mersilene), polyglycolic add (e.g., Dexon),and cross-linked bovine pericardium (e.g., Peri-Guard). To date, nosingle prosthetic material has gained universal acceptance.

Metallic meshes, for example, are generally inert and resistant toinfection, but they are permanent, do not generally adapt in shape as askeletal structure grows, and they shield the healing tissues from thestresses that may be necessary to generate fully functioning tissue.Non-resorbable synthetic meshes have the advantage of being easilymolded and, except for nylon, retain their tensile strength in the body.Their major disadvantages are their lack of inertness to infection, theoccasional interference with wound healing, and that they are oftenlong-term implants. Absorbable meshes have the advantage of facilitatingtissue in-growth and remodeling at the site of implantation, but oftendo not have the short-term or long-term mechanical strength necessaryfor the application.

Both U.S. Pat. No. 4,948,540, granted to Nigam and U.S. Pat. No.5,206,028 granted to Li, disclose a collagen membrane suitable formedical uses. In the case of Li, the membrane is constructed in afashion to make it easier for implantation, by ensuring the membrane isnot transparent, and not slippery. Both patents begin by providing asolution of collagen, which is freeze-dried, cross-linked, and thencompressed. Li then utilizes a second cross-linking, freeze-drying andcompression step. The initial cross-linking step locks the fibers into aspecific orientation. The compression step merely reduces the porositywithin the sheet without inducing fiber migration that wouldsubstantially improve the strength of the composition. A secondcross-linking step is necessary to hold the sheet in its compressedconformation. What is needed is a sheet with improved strength, capableof maintaining its structural competence without the need of multiplefreeze-drying and cross-linking steps.

In U.S. Pat. No. 6,599,524 granted to Li, there is disclosed a membranesheet having oriented biopolymeric fibers. The membrane is manufacturedwith oriented parallel fibers formed around a rotating mandrel. Therotations of the mandrel as the fibers are added results in theorientation of the fibers. The membrane is then compressed to drive outexcess liquid, and cross-linked, resulting in a membrane withdirectionally oriented fibers. This material is only aligned in a singledirection and must be laminated with binding agents in order to create afunctional device. Additionally, such a device does not providegradients such as those seen in natural tissues. What is needed is amethod that allows for layering that occurs at the microscopic as wellas the macroscopic level as part of a one step process and more closelyrepresents the layered structure of natural connective tissues.

Prosthetic devices are used in the repair, augmentation, or replacementof articulating organs. For example, the rotator cuff (i.e., shoulderjoint) is made up by a combination of the distal tendinous portion offour muscles: the supraspinatus, subspinatus, subscapularis and theteres minor. Proper functioning of this tendonous cuff, depends on thefundamental centering and stabilizing role of the humeral head withrespect to sliding action during lifting and rotation movements of thearm. A tear in the rotator cuff tendons is a common injury that can becaused by constant friction from repetitive overhead motion, trauma, orage-related degeneration that can narrow the space between the clavicleand the top of the scapula.

To repair large tears of the rotator cuff, it is desirable to use ascaffold or graft material to help support the damaged tissue and guideits repair. Several types of materials have been used for suchprocedures. Wright Medical (Memphis, Tenn.) markets a product known asGraftJacket, which is manufactured by Lifecell Corporation (Branchburg,N.J.) from human cadaver skin. Human cadaverous tissue products can bedifficult to obtain and have the potential for disease transmission.Tissue Sciences (Covington, Ga.) markets a product known as Permacol,which is comprised of cross-linked porcine dermis. DePuy (Warsaw, Ind.)markets the Restore Patch which is fabricated from porcine smallintestine submucosa. Biomet (Warsaw, Ind.) markets a product known asCuffPatch another porcine small intestine product. The CuffPatch and theRestore Patch products provide biocompatible scaffolds for wound repairbut they are complicated to manufacture, as they require the laminationof multiple layers of submucosal tissues to gain the strength needed forthese applications. Fabrication of such patches from porcine smallintestine submucosa are described in U.S. Pat. Nos. 4,902,508 Badylak etal. and 5,573,784 Badylak et al.

Additional applications for prosthetic devices exist in the form ofmembrane patches. The spinal cord and brain are covered with aprotective membrane that is known as the dura mater. The integrity ofthe dura mater is critical to the normal operation of the centralnervous system. When this integrity is intentionally or accidentallycompromised (e.g., ruptured, severed, damaged, etc.), seriousconsequences may ensue, unless the membrane can be repaired. Typically,dura tissue is slow to heal. To enhance the healing process, graftmaterials can be utilized to guide the regeneration of the tissue.Repairing damaged membranes has largely focused on implantable materialsknown as dural substitutes, which are grafted over the damaged duramater and are designed to replace and/or regenerate the damaged tissue.

Thus, there is a need for an effective dura substitute that would bebiocompatible, sufficiently noninfectious (e.g., purified, etc.) toprevent the transmission of disease, conformable, available in a varietyof sizes, high in tensile strength, inert, suturable, and optionallycapable of forming a water-tight seal.

Researchers have experimented with a wide variety of substances to actas dura substitutes. Autologous grafts of tissue, such as pericardium,can be effective as a dura substitutes; however, autologous tissue isnot always available and it posses additional costs and risks for thepatient. Cadaverous dura mater has also been used but like autologoustissues, cadaverous tissues can be difficult to obtain. Tutogen MedicalInc. (West Paterson, N.J.) markets a product known as Tutoplast duramater, which is obtained from human cadavers. Processed human cadavericdura mater has been implicated in the transmission of cases of the fatalCreutzfeldt-Jakob disease. Other products overcome this shortcoming byusing alternate materials. The Preclude Dura substitute, manufactured byW. L. Gore (Newark, Del.), is an inert elastomeric fluoropolymermaterial. The material is biocompatible but is a permanent implant anddoes not resorb over time. Dural substitutes comprising collagen havebeen also been explored as described in U.S. Pat. No. 5,997,895 (Narotamet al.). Integra Lifesciences Corporations (Plainsboro, N.J.)distributes a product known as DuraGen. The product is manufactured frombovine achilles tendon and is a pliable porous sheet. Although thematerial is resorbable and biocompatible, the integrity of the materialis not sufficient enough to withstand suturing to the wound site.

The present invention overcomes these suturing and other difficulties ofthe materials currently available and provides a structure capable ofbeing adapted to a wide variety of surgical applications.

Other applications for the implantable prosthesis of this invention, inthe form of a surgical mesh, include pelvic floor disorders such uterineand vaginal vault prolapse. These disorders typically result fromweakness or damage to normal pelvic support systems. The most commonetiologies include childbearing, removal of the uterus, connectivetissue defects, prolonged heavy physical labor and postmenopausalatrophy. Many patients suffering from vaginal vault prolapse alsorequire a surgical procedure to correct stress urinary incontinence thatis either symptomatic or latent.

Another embodiment of the present invention is directed to devicesuseful as prosthetic menisci, and in vivo or ex vivo scaffolds forregeneration of meniscal tissue.

The medial and lateral menisci are a pair of cartilaginous structures inthe knee joint which together act as a stabilizer, a force distributor,and a lubricant in the area of contact between the tibia and femur.Damaged or degraded menisci can cause stress concentrations in the kneethereby creating abnormal joint mechanics and leading to prematuredevelopment of arthritic changes.

In the prior art, treatment of injured or diseased menisci has generallybeen both by surgical repair and by tissue removal (i.e., excision).With excision, regeneration of meniscal tissue may not always occur.Allografting or meniscal transplantation is another method ofreplacement, which has been previously tried.

This approach has been only partially successful over the long term dueto the host's immunologic response to the graft and to failures incryopreservation and other processes. Alternately, menisci have beenreplaced with permanent artificial prostheses such as Teflon andpolyurethane. Such prostheses have been selected to be inert,biocompatible, and structurally sound to withstand the high loads whichare encountered in the knee joint. Typically, these permanent implantsdo little to encourage the regeneration of the damaged host tissue.Therefore, what is needed is an improved prosthetic meniscus composed ofbiocompatible materials, which are biocompatible, compliant, durable,and suitable to acts as a temporary scaffold for meniscal fibrocartilageinfiltration and regeneration of the host tissue.

In U.S. Pat. No. 5,184,574 granted to Stone and U.S. Pat. No. 6,042,610granted to Li, there is disclosed a meniscus replacement material,manufactured by shape molding collagen fibers within a mold viaapplication of low pressure by a piston prior to or after drying. Stonerequires the step of applying freezing cycles to the material. Thefibrous materials achieve densities of 0.07-0.5 g/cc. Hydrated fibers atthese density range from a free flowing liquid slurry to a loosedough-like material unable to maintain a shape. Freezing and possiblylyophilizing of the material is necessary to remove it from the mold andcross-linking solutions are applied to it while still in the frozen orlyophilized state so that it does not warp. Fiber orientation may beobtained by applying a rotating force to the piston in order to form acircumferential orientation. However, this orientation occurs only inareas directly in contact with the rotating piston. What is necessary isa fibrous construct with sufficient integrity to be handled without thenecessity of freezing and/or lyophilizing and that can be implantedwithout the requirement of cross-linking, if desired. Additionally, thisconstruct lacks any consistency throughout the thickness of itsstructure, being able to create oriented fibers only at the periphery.

Another embodiment of the present invention is directed to devicesuseful as prosthetic ligament, and in vivo or ex vivo scaffold forregeneration of ligament tissue and to methods for their fabrication.

The anterior cruciate ligament (ACL) of the knee functions to resistanterior displacement of the tibia from the femur during flexure. TheACL also resists hyperextension and serves to stabilize the fullyextended knee during internal and external tibial rotation. Partial orcomplete tears of the ACL are common. The preferred treatment of thetorn ACL is ligament reconstruction, using a bone-ligament-boneautograft (e.g., from the patient's patellar tendon or hamstringtendon). Cruciate ligament reconstruction generally provides immediatestability and a potential for immediate vigorous rehabilitation.However, ACL reconstruction is not ideal; the placement ofintraarticular hardware is required for ligament fixation; anterior kneepain frequently occurs, and there is an increased risk of degenerativearthritis with intraarticular ACL reconstruction. Another method oftreating ACL injuries involves suturing the torn structure back intoplace. This repair method has the potential advantages of a limitedarthroscopic approach and minimal disruption of normal anatomy. Adisadvantage of this type of repair is that there is generally not ahigh success rate for regeneration of the damaged tissues due to thelack of a scaffold or other cellular inductive implant.

Another embodiment of the present invention relates to devices useful asa prosthetic intervertebral disc. The intervertebral disc plays animportant role in stabilizing the spine and distributing the forcesbetween the vertebral bodies. In the case of a damaged, degenerated, orremoved disc, the intervertebral space collapses over time and leads toabnormal joint mechanics and premature development of arthritis.

In the prior art, discs have been replaced with prostheses composed ofartificial materials. The use of purely artificial materials in thespine minimizes the possibility of an immunological response. Suchmaterials must withstand high and repeated loads seen by the spinalvertebral joints, early attempts focused upon metallic disc implants.These efforts met with failure due to continued collapse of the discspace and or erosion of the metal prosthesis into the adjacent bone.

SUMMARY OF THE INVENTION

The current invention is directed to a general prosthesis, which, whenimplanted into a mammalian host, undergoes controlled biodegradationaccompanied by adequate living cell replacement, such that the originalimplanted prosthesis is remodeled by the host's cells before it isdegraded by the host's enzymes and/or by hydrolosis. The device of thesubject invention is structurally stable, pliable, semi-permeable, andsuturable.

Embodiments of this invention can be utilized to repair, augment, orreplace diseased or damaged organs, such as rotator cuff injuries, duradefects, abdominal wall defects, pericardium, hernias, and various otherorgans and structures including, but not limited to, bone, periosteum,perichondrium, intervertebral disc, articular cartilage, dermis,epidermis, bowel, ligaments, tendon, vascular or intra-cardiac patch, oras a replacement heart valve.

The device if this invention could be used for sling procedures (e.g.,surgical methods that place a sling to stabilize or support the bladderneck or urethra). Slings are typically used to treat incontinence.Additionally, in the form of a surgical mesh, the device can be used forsuch applications as hernia and dura repair.

In another embodiment, this invention provides a ligament repair orreplacement prosthesis that is biocompatible, is able to withstand ACLforces, and promotes healing of the injured tissues by acting as ascaffold for cellular infiltration. Another embodiment of this inventionis to provide an improved disc replacement or prosthesis that isbiocompatible, does not interfere with normal vertebral segment motion,is able to withstand normal spinal column forces, does not wear into thesurrounding bone, promotes regrowth of intervertebral disc material andacts as a scaffold for fibrocartilage infiltration.

The tissue repair implant of this invention, functioning as a substitutebody part, may be flat, tubular, hollow, solid, or of complex geometrydepending upon the intended use. Thus, when forming the structure of theprosthesis of this invention, a mold or plate can be fashioned toaccommodate the desired shape.

Flat sheets may be used, for example, to support prolapsed orhypermobile organs by using the sheet as a sling for those organs ortissues (e.g., bladder or uterus). Tubular grafts may be used, forexample, to replace cross sections of tubular organs such as esophagus,trachea, intestine, and fallopian tubes. These organs have a basictubular shape with an outer surface and a luminal surface. In addition,flat sheets and tubular structures can be formed together to form acomplex structure to replace or augment cardiac or venous valves andother biological tissue structures.

The tissue repair implant of the present invention may be renderedporous to permit the in-growth of host cells for remodeling or fordeposition of the collagenous layer. The device can be rendered“non-porous” to prevent the passage of fluids if necessary or theporosity can be adjusted to create a membrane capable of selectivepermeability. The degree of porosity will affect mechanical propertiesof the implant, and these properties are also affected by processing (aswill be discussed).

The mechanical properties include mechanical integrity such that thetissue repair implant resists creep for the necessary period of time,and additionally is pliable (e.g., has good handling properties) andsuturable. The term “suturable” means that the mechanical properties ofthe layer include suture retention, which permits needles and suturematerials to pass through the prosthesis material at the time ofsuturing of the prosthesis to sections of native tissue. Duringsuturing, such prostheses must not tear as a result of the tensileforces applied to them by the suture, nor should they tear when thesuture is knotted. Suturability of tissue repair implant, i.e., theability of prostheses to resist tearing while being sutured, is relatedto the intrinsic mechanical strength of the prosthesis material, thethickness of the prosthesis, and the tension applied to the suture. Themechanical integrity of the prosthesis of this invention is also in itsability to be draped or folded, as well as the ability to cut or trim orotherwise shape the prosthesis.

In another embodiment of the invention, reinforcing elements (e.g.,threads, fibers, whiskers, textiles, etc.) are incorporated into thetissue repair implant for reinforcement or for different rates ofremodeling. Thus, the properties of the tissue repair device can bevaried by the geometry of the thread used for the reinforcement.Additionally thread constructs such as a felt, a flat knitted or wovenfabric, or a three-dimensional knitted, woven or braided fabric may beincorporated between layers or on the surface of the construct. Porous,non-fibrous sheets of polymer foam may also be incorporated betweenlayers or on the surface of the construct. Such polymer foams can bemade by methods known in the art such as particulate leaching or solventfreeze-drying methods.

An embodiment of the present invention may be made by the followingsteps: providing a mixture comprising a plurality of fibers, alubricant, and a suspension fluid, with the suspension fluid filling avoid space between said fibers and subjecting said mixture to at leastone compressive force. The compressive force causes the migration andalignment of said fibers; and may remove substantially all of thesuspension fluid from said mixture. The mixture may further comprise abiologically active agent, or a reinforcing agent.

Additionally, the compressive forces may reduce the void space betweenthe fibers, and the lubricant may assist fiber movement duringcompression, and be in the form of a liquid or a solid, and may beprovided in a carrier fluid. The suspension fluid flow may also causeplates of oriented fibers to be formed.

The compressive force may be applied by a molding surface, therebycreating a shaped fibrous member in said mold. Additionally, oralternatively, the material may be machined, allowing the fabrication ofcomplicated shapes.

In a preferred embodiment, at least a portion of said compressed mixturemay be cross-linked by exposure to a cross-linking agent. This processwill affect the strength and resorption rate of the implant.Additionally, the strength may be tailored by a reinforcing element,such as particulates, threads, fibers, whiskers, textiles, rods, meshes,or combinations thereof. The function or properties of the implant mayalso be affected by additives, such as ceramics, polymers, cells,biologically active agents, liquids, surfactants, plasticizers, andcombinations thereof.

DESCRIPTION OF THE DRAWINGS

FIG. 1 depicts fibrous dough prior to and after compression.

FIG. 2 depicts a change in fiber orientation and inter-fiber void spaceas the fibrous dough is compressed.

FIG. 3 depicts fibrous dough prior to and after compression.

FIG. 4 depicts compression of fibrous dough as it passes throughrollers.

FIG. 5 depicts three-dimensional compression of fibrous dough.

FIG. 6 depicts compression of a cylindrical mass of fibrous dough.

FIG. 7 depicts incorporation if reinforcing materials within compressedfibers.

FIG. 8 depicts incorporation of particulates, biologics within thecompressed fibrous matrix.

FIG. 9 depicts incorporation of microstructures within the compressedfibrous matrix.

FIG. 10 depicts a hemostatic tract plug of compressed fibrous matrix.

FIG. 11 depicts hemispherical cups of compressed fibrous matrix.

FIG. 12 depicts a selectively compressed ring of fibrous matrixsurrounding a non-compressed fibrous matrix.

FIG. 13 depicts selective compression of a fibrous matrix.

FIG. 14 depicts compressed fibrous constructs useful surgicalapplications.

FIG. 15 depicts the surgical application of a compressed fibrousconstruct.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

Embodiments of this invention include compressed, biodegradable, fibrouscompositions for application to a tissue site in order to support,promote or facilitate new tissue growth. One aspect of this invention isa fibrous component (e.g., collagen, elastin, chitosan, alginate,hyaluronic acid, polyglycolic acid, polyurethane, silk, etc.; seetable 1) that provides unique mechanical and physical properties, aswill be discussed. Such fibrous components in slurry form may bepre-processed into a fibrous dough or paste by removal of a portion ofsuspension fluid, as known in the art, prior to formation into acompressed conformation, as will be disclosed. An example is in the formof an interlaced matrix described in U.S. patent application Ser. No.10/601,216 filed on Jun. 20, 2003 and assigned to the same assignee ofthe present invention, which is incorporated by reference herein. Thematerial is a natively cross-linked collagen such as Semed F produced byKensey Nash Corporation (Exton, Pa.).

The fibrous dough is dehydrated/desolvated by applying a compressiveforce in such a manner as to reduce the inter fiber space by removing atleast a portion of the suspension fluid. In a preferred embodimentsubstantially all of the suspension fluid is removed. Unlike unalteredor natural matrices (e.g., dermis, small intestine submucosa, etc.), thethickness, porosity, fiber-density, fiber-orientation, fiber-length,fiber composition and component-ratio (e.g., Collagen to Elastin ratio),as a non-limiting example, can be controlled with the current invention.

To improve the migration of fibers and prevent clumping during thecompressive process it is preferred to incorporate a percentage (e.g.,0%-50% by mass of fibers) of one or more lubricants (e.g., biocompatibleoils, hydrogels, liquid polymers, low-molecular weight polymers,glycosaminoglycans, surfactants, waxes, fatty acids, fatty acid aminesand metallic stearates such as zinc, calcium, magnesium, lead andlithium stearate, etc.) into the fibrous dough suspension. A lubricantis defined as a substance, which is capable of making surfaces smooth orslippery. These characteristics are due to a reduction in frictionbetween the polymers to improve flow characteristics and enhance theknitting and wetting properties of compounds. Said lubricant may beliquid or solid and may be suspended or dissolved in a carrier solvent(e.g., water, alcohol, acetone, etc.). Additionally the lubricant mayonly become lubricious under compressive force or change in temperature.The lubricant may remain in its entirety in the final invention; may bepartially removed in the dehydration/desolvation process; or, may bewashed out or removed by methods known in the art during furtherprocessing. Lubricants that remain in the final invention may bebiologically active agents or may form microstructures. Preferredlubricants include Tween-80, hyaluronic acid, alginate, glycerin orsoluble collagen with the most preferred being acid soluble collagensuch as Semed S produced by Kensey Nash Corporation (Exton, Pa.).

Additional ways in which to add lubricity include physically orchemically altering the surface of the fibers making up the composition.Such alterations can be achieved through chemical or physical attachmentof a lubricious substance to the fibers, temperature induced phasechanges to the surfaces of the fibers or partial solubilization of thefibers through alteration of the pH and/or conductivity of the freefluid or use of a percentage of solvent for the fibers within the freefluid. Other methods of creating lubricity are known to those skilled inthe art, and are embraced by this disclosure.

During the compression step of the fibrous dough, the fibers alignthemselves into layered or plate-like structures. As the inter fibervoid space is collapsed, the displaced fluid is forced outward andbegins to flow out of the device. The flow may play a role in aligningthe fibers in that direction. The rate of flow is directly affected byrate and duration at which compression occurs. This phenomenon occursthroughout the structure and results in aligned fibrous layers or platesseparated by fluid planes. These planes facilitate migration within thestructure, allowing the fibers within a single layer to move withoutinterference from fibers in a different layer.

The compression induced fluid migration may occur three-dimensionally,thereby dissecting planes in the structure as it runs into resistance.Additionally the fluid may be forced through narrow passageways in thefibrous mats and begin creation of a new plane at a different levelwithin the construct. Thus it is possible to create a structure whereinthe planes do not traverse the entire length of the device, but insteadexist as multiple fissures located randomly within the construct andeach fissure can be defined by fibrous plates having an aligned fiberorientation unique from that of neighboring fissures. The platesthemselves may be organized in a random, oriented, or aligned fashion.As compression continues, the lubricant reduces the friction, allowingthe aligned fibers within the plates or planes to slide across eachother and nest in the most compact orientation. Additional compressionbrings the plates of fibers in closer contact, allowing them to becomelocked into a compact anisotropic structure, although the material maybe isotropic in two dimensions.

Unlike existing state of the art sheets, this layering occurs at themicroscopic as well as the macroscopic level as part of a one stepprocess and more closely represents the layered structure of naturalconnective tissues. Additionally, the amount of fiber compaction withina plate or layer and the spacing between the plates or layers can becontrolled by the force applied and the amount of time allowed forequilibration at a specific force. The preferred force applied is from0.01 tons/square inch to 100 tons/square inch with the most preferredforce being in the range of 0.2 tons/square inch to 2.0 tons/squareinch. This amount of force is in excess of state of the art methods usedmerely to extract fluid and concentrate the fibers into workabledough-like material. Existing methods do not induce fiber migration orlayer formation. Devices created under such conditions as describedabove do not require additional steps such as freezing and/orcross-linking within molds to be handled. The preferred amount ofequilibration time is in the range of about less than one minute to morethan 500 minutes with a more preferred range of about 1 minute to 60minutes.

The use of wicking materials such as paper towels/sponges or fluidremoval systems such as screens or vacuum systems prevent excessivepooling of fluid in any single area of the structure during compression.If fluid is allowed to accumulate, it can create craters or voids withinthe structure. If the fibers surround these pools of fluid succumb tothe compressive forces, a rip or discontinuity in the structure willform as the fluid is forcibly expelled. Strategic location of fluid exitpores within a mold can be used to create unique directional flows thatin turn align the fibers within a layer or plate. In this way the fibersforming plates at each level can be oriented in the same direction orturned at any conceivable angle to each other. Although orientation offibers from plate to plate may be organized or random, fiber orientationwithin a plate is organized with the fibers running predominantlyparallel to each other. Molds with fluid vacuum assist further improvecontrol of fiber orientation. Additionally, materials such as threadsand screens provide avenues for fluid escape. As the fluid flows alongthe length of the threads and screens, the fibers adjacent to them arealigned parallel to them. Use of porous rods or porous hollow tubes thatcan be extracted or left in place as reinforcement can also be used tofacilitate uniform fluid removal. If the fluid extraction tubes areremoved, long channels will be left that can be utilized for purposessuch as suture line conduits.

As the inter fiber space is reduced and the free fluid within the doughis expelled, the overall porosity of the compressed composition isreduced towards a theoretical zero point. The amount of porosity as wellas the size of the pores dictates whether the device functions as atissue matrix or barrier. Additionally, the physical/mechanicalproperties are highly influenced by the amount of inter fiber space.Another factor affecting the mechanical and physical properties of thecomposition is the use of additives (e.g., surfactants, plasticizers,particulates, porosifiers, meshes, etc.).

In a preferred embodiment, the method of preparing the high-densityfibrous matrix involves: providing a fibrous material; contacting saidfibrous material with a suspension fluid and a lubricant; applying acompressive force within one or more dimensions that partiallydehydrates/desolvates the fibrous material. Subsequently, the fibrousmaterial may be cross-linked. It may be further desirable to provide adirected means of egress for the suspension fluid during compression, aspreviously discussed. Additionally use of a fibrous suspension havinginterlaced, interlocked fibers may be desirable.

In another embodiment, the partially dehydrated fibrous matrix is fullydried (e.g. vacuum dried, freeze-dried, air-dried.) after which it maybe cross-linked. It may be further desirable to rehydrate/resolvate thefibrous matrix to facilitate incorporation of cross-linking agents,plasitisizers, surfactants, biologically active agents, microstructures,cells or other materials. If desired the sheet may again be dried.

Any method of compression known by those skilled in the art isconceivable for this invention, including, but not limited to, usinghydraulically or pneumatically powered platens or pistons to compressthe fibrous matrix material. Other methods include but are not limitedto using a screw or an arbor press to compress the material, usingcentrifugation to extract fluid and compress the fibers, or forcing thematerial between rollers.

The structure of the fibrous matrix material is also influenced by theamount of compressive force applied to the material. The amount ofcompression may change the porosity of the fibrous matrix material. Thepore size distribution will also be affected by the amount ofcompression as the fibrous matrix material may be compressed so thatonly certain areas have collapsed, or so that all areas collapse. Thedirection of compression in relationship to the original structure ofthe fibrous matrix material will also affect the structure of thecompressed fibrous matrix material. For example, if the initial fibrousmatrix material has long parallel fibers, a force applied could be usedto force the fibers together in a parallel fashion or bunch up thefibers as the force attempts to shorten the length of the fibrouscomposition.

Compression of the fibrous matrix material can be controlled to createvarious structural patterns within the material; likewise, themechanical properties of the material may be altered to meet specificrequirements. The amount of compression is directly related to the tearstrength of the material. If a medical device fabricated from thecompressed material is not in the form of a sheet, the compressedmaterial can be compressed three-dimensionally to form the desiredshape. If the medical device is axially loaded, the compressed materialmay be compressed in one direction to optimize the mechanical propertiesof the material in that direction.

If not compressed initially into the final shape, after being compressedand removed from the compression device, the fibrous matrix material maybe machined into a new shape or design with various features. Machiningprocesses are well known to those skilled in the art. (e.g., punching,coring, milling, sawing, lathing, etc.) Additionally, the compressedfibrous matrix may function as a component of a larger device and if notattached during the compression step, may be attached to components bymethods known to those in the art (e.g., gluing, stapling, sewing,etc.).

The inventors have discovered that after the compressivedehydration/desolvation process the resultant material has mechanicalproperties, including tear strength, superior to those of non-compressedmaterials that have been cross-linked. Not being confined to a singletheory, it is believed that the high compressive forces will create weakchemical linkages aside from the physical interaction of the fibers.This permits the current invention to be utilized in applications thatinitially require specific tear strength but where it is desirable forthe device to be quickly degraded away after fulfilling its initialfunction such as dura repair. The current invention can be cross-linked,either chemically (e.g., EDC) or by non-chemical methods (e.g.,dehydrothermal (DHT)) know to those skilled in the art, for applicationsrequiring strength for an extended period of time, such as herniarepair.

The inventors have further discovered that a non-compressed or mildlycompressed sheet can be cross-linked, completely or only at the surface,by a first method after which it is fully compressed and cross-linked bya second method. The first cross-linking restricts motion of the fibersduring the compression step, retarding an increase in the footprint ofthe sheet. Even thought the sheet is cross-linked in the non-compressedstate, the addition of a lubricant facilitates migration and shifting ofthe partitions making up the sheet. This allows thick sheets to achievethe same fiber density per unit volume as thin sheets.

Highly compressed sheets of collagen fibers placed into cross-linkingsolutions have formed a tough cross-linked skin around a minimallynon-cross-linked center. The center of such sheets are easily separatedforming a shell, pocket or bladder. The permeability of the bladdersvaried depending upon the initial compression. Low compression producedbladders that slowly allowed dyed fluid to exude. Moderate compressionallowed water to pass through but filtered out the larger dye molecules.High compression created a barrier to fluid water but slowly allowed theescape of water vapor. Such a phenomenon was not evident in DHTcross-linked sheets.

Such devices would be useful for tissue engineering applicationsassociated with bladder, intestine, tendons, ligaments and vessels, aswell as the creation of rotator cuff patches, hernia repair sheets,orbital implant coverings, graft wraps and the formation ofanti-adhesion devices. The shell of material could be filled withceramics or polymers useful in bone repair or used as containmentdevices for injection of settable polymers or ceramics. Additionally,the center could be filled with fluids prior to or after implantationfor applications such as controlled drug delivery or the creation ofshock absorbing vessels useful for breast implants, fat pad replacementor meniscus and disc repair or replacement.

Restricted contact of cross-linking solutions with the surfaces ofcollagen devices control the degree of cross-linking in fibrous,non-fibrous, compressed and non-compressed materials. For example,restricted contact can be achieved by placing shaped, fully hydrated,collagen dough into a cross-linking solution. The cross-linking solutionslowly displaces hydration fluid at the periphery but does notimmediately come into contact with the hydrated material in the center.As the material continues to sit in the cross-linking solution agradient begins to form with a greater amount of cross-linking occurringat the surface and lesser amounts of cross-linking occurring toward thecenter.

Additionally, a second type of cross-linking could be introduced afterdrying to create a bi-phasic cross-linking (e.g., DHT, chemical vapors,radiation). Devices having such unique cross-linkings would be useful intissue-engineering applications involving multi-phasic tissues such ascartilage and skin or could function as in-vivo cell culture vesselscapable of protecting foreign cells, such as islet cells from adifferent person or animal, from attack by the recipients' immunesystem.

The central portion of units cut from compressed collagen sheets havingonly the surface cross-linked swell when in contact with excess aqueousfluids. A small amount of fluid hydrates the sheet and creates thinflexible units. Only after being placed in contact with excess fluiddoes the sheet begin to swell. The swelling can be delayed by minutes tohours depending upon the initial thickness, magnitude of compression,and the amount of cross-linking at the surface. This creates a largecentral porosity suitable for cell migration and/or delayed drug orbiologics delivery, centered between two low-porosity protective sheets.Such a device would also be suitable in applications requiringimplantation through a small opening that will swell to full size afterbecoming fully hydrated by body fluids.

The fibrous matrix material may be compression molded into an initial orfinal design of a medical device. If the device has complicatedgeometry, various features may be machined after compression molding.The material and mechanical properties of the final device can bealtered by the temperature of the molds, the amount of overallcompression, the design of the mold, etc. The fibrous matrix materialmay be compressed before molding, or all the compression may occurduring the molding process. The direction of compression before orduring compression molding will also affect the mechanical properties ofthe device. For example, a cylinder of fibrous dough material may bethree-dimensionally compressed to improve the mechanical properties andthen compression molded into a threaded bone screw. Additionally, thecylinder of fibrous material could be compressed into a cone shapeproviding a gradient of compression. Such gradients would be useful formulti-phasic tissue or multi-phasic drug delivery.

The implantable prosthesis of the present invention may be sterilized byany method known in the art. (e.g., exposure to ethylene oxide, hydrogenperoxide gas plasma, e-beam irradiation, gamma irradiation, etc.) Thesterilization minimizes the opportunity of infection to occur as aresult of the implant.

In the preferred embodiment of the invention, the fibrous prosthesis ismanufactured from a resorbable material, although this is not meant toexclude the use of non-resorbable polymers, minerals and metals withinthe final structure.

Different polymers, molecular weights, additives, processing methods,cross-linking methods and sterilization methods can be used to controlthe resorption rates of resorbable polymers and is well know by thoseskilled in the art. For example, reconstituted collagen fibers degradefaster than natively cross-linked collagen fibers and collagen that hasnot been cross-linked degrades faster than cross-linked collagen.Additives such as ceramics capable of increasing the localized pH alsoincrease the rate of degradation, as do chemotactic ground substancesthat attract cells to the localized area. Resorption rates can beadjusted to be shorter for applications that require mechanical strengthfor only a short period of time or longer for applications that requiremechanical strength to be present for a longer duration. Examples ofresorbable polymers that can be formed into fibers and used to form theprosthesis are shown in Table 1. These materials are only representativeof the materials and combinations of materials that can be used asprosthetic material and this table is not meant to be limiting in anyway.

For the purposes of promoting an understanding of the principles of thisinvention, reference will now be made to the embodiments illustrated inthe drawings and specific language will be used to describe theembodiments and elements of the embodiments. It must be understood thatno limitation of the scope or applications of the invention is therebyintended. For ease of understanding, fibers are represented in thedrawings by simple crossed lines, by no way does this indicate that theymay not be interconnected, interwoven, interlaced or entangled, or thatthe final structure is porous or non-porous, organized or random, and/orreticulated, except as otherwise noted. In theory, the compressedfibrous structure could in fact be produced through the compression of asingle continuous fiber.

Referring now to the drawings, FIG. 1 shows the fibrous matrix materialbefore and after compression. Before compression, shown in FIG. 1A, thefibrous matrix material 100 comprises a large percentage of void spacesurrounding the fibers 110. The fibers 110 form a structure composedmostly of inter fiber void space 120. After being compressed, shown inFIG. 1B the compressed porous matrix material 130 contains the sameamount of fibrous material 140; however, the sacrificed, inter fibervoid space 150 has resulted in a reduced porosity in the material. Itshould be noted that the inter fiber void space in this figure and allother figures may contain a lubricant as has been discussed.

In another embodiment depicted in FIG. 2A, the fibrous matrix material200 is placed between two compressive devices 210 (e.g., platens,pistons, etc.), which may or may not be heated or cooled. Heating can beused for such purposes as to modify the fibers (e.g.,—denature, soften,melt), increase the rate of fluid evaporation, fuse the fibers oncecompressed, or improve the activity of any lubricant. Cooling can beused for such purposes as protecting the fibers from excessive heatduring compression or to induce phase change or thickening of thesuspension fluid and/or lubricant. The fibers 220 and the inter fibervoid space 230 define the structure of the fibrous matrix material. InFIG. 2B, the top compressive device 215 is lowered to compress thefibrous matrix material 240 while the compressive device 210 remainsstationary. A gradient is formed starting at the top of the materialwhere fibers 250 are forced together, reducing the interfiber void space230, while the fibers 220 in the lower part of the material retain theirconformation. This can be employed to create an implant for biphasictissues such as bone or cartilage. Two gradients can be formed bycompressing the fibrous matrix material 260 with both compressivedevices 215 at the same time, as shown in FIG. 2C. The top and bottomsurfaces have a majority of compressed fibers 250. The next top andbottom layer of fibers 280 will be mildly compressed and have a reducedinter fiber void space 270. The middle of the material 260 will havefibers 220 that maintain their original inter fiber void space 230. Thiscan be employed to create an implant for a triphasic tissue such as theskull that transitions from cortical bone to cancellous bone and back tocortical bone. As shown in FIG. 2D, if compressive devices 215 continueto exert force the material 290 could be evenly compressed with nogradients. The compressed fibers 250 and inter fiber void space 295 willbe evenly distributed, or nearly so, through the material 290. Continuedcompression by compressive devices 215, as shown in FIG. 2E initiatesmigration of fully compressed fibers 296 in the material 297. Thisfurther reduces the inter fiber void space 298. This is useful in thecreation of sheet implants having superior strength and finelycontrolled porosity to replace those currently manufactured for suchapplications as dura, tendon and hernia repair.

It is envisioned that desired percentages of porosity or desired poredistribution can be controlled based on the amount and method ofcompression. Specific pore volumes or densities may promote differenttypes of tissue ingrowth (e.g., bone or vascular tissue ingrowth). Basedon desired porosity or density, the fibrous matrix material may act as acellular scaffold for various uses in tissue engineering.

In another embodiment as illustrated in FIG. 3A, an amorphous mass offibrous dough 300 containing fibers 310 and inter fiber void space 320is compressed to form an anisotropic sheet material 330 shown in FIG.3B. The fibers 340 begin to align in the radial direction as force 350induces migration of the fibers 340 collapsing the inter fiber voidspace 360.

Another form of compression is illustrated in FIG. 4. An amorphous mass400 containing fibers 410 and inter fiber void space 420 is drawnthrough rollers 430. This drawing motion compresses and aligns fibers440 while simultaneously reducing the inter fiber void space 450. Therollers could also be aligned circumferentially around the mass and usedto draw the material into an elongated cylinder (not shown).

Another form of compression utilizes centrifugal force to compressfibers in an outward direction onto a porous structure. For example, thefibers could be forced out against a spinning porous drum creating acylinder of compressed fibrous material (not shown). The drum couldcontain any number of contours or structures that would formcorresponding negatives and positives in the fibrous material. Such amethod could be used to create detailed anatomical structures such asthe cheek, nose or ear. Additionally, this process could be used tocreate multi-layered constructs or embed materials such as sutures,particulates or meshes into the fibrous constructs. In another preferredembodiment, the above formed multi-layer construct is placed over amandrel and further compressed creating a structure useful for tissueengineering applications such as vascular grafts, where each layercorresponds to the individual layers within an artery. In anotherembodiment, the above mandrel is replaced by a series of fibers orthreads, which may or may not be woven or spun together, wherein thecompressed fibrous material interpenetrates/interdigitates the series offibers or threads, locking them into a conformation suitable for tendon,ligament or muscle repair.

In another embodiment as illustrated in FIG. 5, a sphere 500 of fibrousmatrix material is three-dimensionally compressed by force 510. Fibers520 separated by inter fiber void space 530 create the sphere's 500structure. After being compressed, the porosity, inter fiber void spaceand size of the sphere 540 are decreased. Unlike two-dimensionalcompression, the fibers 550 have not collapsed into thin layers. Thethree-dimensional compression caused each fiber 550 to fold or coil asthe inter void space 560 was reduced. This embodiment could be used as adevice to promote staged delivery of biologically active agents or itcould be split in half to create a chin or cheek implant, for example. Apolymeric material could be placed in the center to release abiologically active agent (not shown). This embodiment may also be usedto create a cell based implant wherein the cells supported in thenon-compressed center of the device are protected from the body's immunesystem by the collapsed porous exterior. The center could also behollowed out by using a central core material (e.g., ice, polymer, salt,etc) that could function similar to a porosifying agent and be removedafter compression and replaced with cells (not shown). This would beparticularly useful in supporting and protecting transplanted tissue(autograft or xenograft) such as islet cells capable of producinginsulin. While the compressed fibers 550 would prevent immune cells fromentering the sphere 540 and destroying the islet cells, oxygen andnutrients would readily pass through the compressed inter fiber space560. In turn, waste product and insulin would pass out of the sphere.

A modified three-dimensional compression is illustrated on a cylinder600 of fibrous matrix material in FIG. 6. Like the sphere 500, thecylinder 600 is composed of fibers 610 separated by inter fiber voidspace 620. Compression can be applied to the cylinder 600 by applyingforce around the circumference of the cylinder 600 while restrictingelongation (or increasing) of its height. This type of three-dimensionalcompression would cause the compressed cylinder's 630 fibers 640 to packtogether as the inter fiber space 650 is reduced. If elongation isencouraged, the fibers would draw out as the inter fiber space isreduced (not shown). Depending on the amount of compression, anddirection of fiber migraton, the fibers 640 could define thin channelsrunning parallel to each other throughout the height or width of thecylinder 630. Devices like this would be useful as orthopedic rods ornerve guides. Placement of one or more removable solid rods in thecenter of the mass would allow for the formation of one or more lumenwithin the cylinder. Uses would include tissue engineering of vessel andnerves as well as any other tubular tissue.

In another embodiment, the compressed fibrous material containsreinforcing materials such as long threads, meshes, rods, and otherfibers. The migration of the fibers under the compressive force mayconfine, and lock the reinforcing material within a spatialconformation. This could retard the reinforcing material from migratingwithin, or dissecting from, the compressed fibrous material. Thisphenomenon can be used to alter mechanical properties (e.g., tearstrength) of the construct. Additionally, the compressed fibrousmaterial may improve the biocompatibility of the reinforcing material(e.g., improved cellular migration within or adhesion to a mesh). FIG.7A shows a construct 700 comprised of an embedded mesh/screen 710embedded/entangled within the fibers 720.

The reinforcing material may be centered within the construct, locatedon or just below one or more surfaces or interspersed throughout theentire construct. As an example shown in FIG. 7B, the fibrous material730 may be compressed over a bone screw 740 creating a coating 750approximating the shape of the screw that is used to temporarily orpermanently hide the material of the screw from the body's immunesystem. The coated implant 760 is useful as an improved interferencescrew. Additionally, the reinforcing material may be porous and permitinterdigitation of the fibers. This porosity also assists in the removalof fluid/lubricant during compression. If desired, vacuum can be used tofacilitate drawing of fluid and fibers into the porosity. The lubricantmay itself function as a bridging agent locking the fibrous coating tothe porous reinforcing material.

In another embodiment, as seen in FIG. 8, a device 800 containingcompressed fibers 810 are used to control the location and delivery ofbiologically active agents 820 (e.g., growth factors, cytokines, genes,hormones, BMP, drugs, cells, viruses, etc., see Table 2). The uniquecompressive forces used to create the device can be used to control flowof fluid (e.g., blood, interstitial fluid, etc.) within the deviceduring processing, allowing for tailored release properties. Thebiologically active agents 820 could be located within or supportedbetween the compressed fibers 810 making up the device 800.Additionally, the biologically active agents 820 could be physically orchemically attached or bonded to the fibers 810 or suspended within ahydration fluid that is supported within the inter fiber void space 830.This hydration fluid may contain a soluble polymer that suspends orbinds the biologically active agent. Additionally, the hydration fluidcontaining the soluble polymer may be removed leaving the solublepolymer as a coating on the compressed fibers or microstructuresuspended within the inter fiber void space between the compressedfibers.

In another embodiment, also shown in FIG. 8, the compressed fibers 810are used to control the location and orientation of reinforcing and/orbiologically active particulate components 840 compounded into thefiberous material (e.g., tricalcium phosphate, hydroxyapatite, calciumsulfate, autologous bone graft, allograft bone matrix, DBM, polymers,microspheres, etc; additionally, see Table 3). The compressed fibers 810may confine, and lock the particulate components 840 within the interfiber void space 830. This retards the particulate from migrating withinor disassociating from the compressed fibrous device/construct 800. Whenadding particulate, the addition of a lubricant facilitates movement ofthe particulate within the construct during the compression steppreventing stratification or clumping of the particulate in the finalproduct. Additionally, the lubricant can be left within the polymer as avelour or coating entrapping the particulate.

It should also be noted that the use of reinforcing materials (e.g.,polymer mesh, titanium screens, TCP, etc.) or addition of biologicallyactive agents (e,g, growth factors, DBM, cells, drugs, etc.) may beemployed as or in a fiber, rod, thread, wire, particulate, microsphere,fragment, suspension, emulsion or other addition. These materials can beuniformly distributed throughout the compressed fibrous construct, or ifdesired, stratified or concentrated to specific areas of the construct.This can be easily achieved by placing depots of materials between twoor more layers of fibrous material prior to compression, as well as bythe methods previously discussed.

It is also conceived that in one embodiment of this invention thematerial can contain an additive that can be used to help deliver orretain the previously described biologically active agents. As anexample shown in FIG. 9, the inter fiber void space 910 of the grosscompressed fibrous structure 900 could be invested with a chemotacticground substance 920, such as the velour of hyaluronic acid suspendedbetween the compressed fibers 930. A velour could accomplish severalbiochemical and biomechanical functions essential for wound repair. Forexample, since hyaluronic acid is extremely hydrophilic, it may bevaluable for drawing body fluid (e.g., blood, bone marrow) or otherfluid-based biologically active agents into the fibrous device. Uponhydration, the hyaluronic acid can become an ideal carrier forpharmacological or biologically active agents (e.g., osteoinductive orosteogenic agents such as the bone morphogenetic protein (BMP) and otherbone-derived growth factors (BDGF)) by providing for chemical bindingsites, as well as by providing for mechanical entrapment of the agent asthe velour forms a hydrogel. It is further conceived and shown in FIG.9B that the velour 940 extend beyond the boundaries of the compressedfibers 950, creating a layer of microstructure attached to thecompressed fibrous structure. This bi-phasic device 960 is useful as anadhesive bandage when the microstructure is a tissue adhesive agent.

In another embodiment, the material may be cross-linked to impartimproved characteristics such as: mechanical strength (e.g.,suturablity, compression, tension, etc.), and biodurability (e.g.,resistant to enzymatic and hydrolytic degradation). This may beaccomplished using several different cross-linking agents, or techniquesknown to those skilled in the art (e.g., thermal dehydration, radiation,EDC, aldehydes (e.g., formaldehyde, glutaraldehyde, etc.), naturalagents such as genipin or proanthocyanidin, and combinations thereof).

In another embodiment, a sheet produced by methods previous describedmay be rolled, contoured or shaped prior to cross-linking to lock thesheet into a unique spatial configuration, for example, a spiralconfiguration may be created having a plane separating each successiverevolution of the sheet. The plane provides unique compressivequalities, that when combined with the compressive qualities of thecross-linked compressed fibers, is ideal for applications receivingdirectional compressive loads. These applications include but are notlimited to joint meniscus, intervertebral disk and articular cartilage.In another embodiment, the plane formed by the spiral configuration canbe filled with materials to enhance its mechanical or biologiccharacteristics (e.g., reinforcing materials, particulates, biologicallyactive agents, natural and synthetic polymers).

In another embodiment, fibers can be compressed directly into a moldthat approximates the gross anatomy of a tissue or organ (e.g., bloodvessel, heart valve, ear, nose, breast, finger-bones, etc.) after whichthe construct may be cross-linked. The reduced inter fiber void space ofthe compressed fiber provides superior shape holding characteristics dueto the unique resistance to fiber disassociation. A star-shapedstructure 1000 shown in FIG. 10 illustrates a possible design for ahemostatic tract plug made possible by the superior shape-holdingcharacteristics of the present invention. Preferably such a device isnot cross-linked to provide the shortest resorption time postimplantation. Upon exposure to body fluids the construct swells,creating a tampanode effect. Due to the compressive forces used duringfabrication, the fibers do not readily disassociate from the unit. Ifcross-linking is desired, it is preferable to cross-link the outersurface only so that the interior fibers are able to swell. As thecenter of the device swells, the star's concave portions are pushed outcreating a cylinder that seals the wound site.

Such a swellable device has applications which include the occluding ofother openings, ducts or lumens in the body (both natural andartificial) and that it can be utilized to deliver biologically activeagents and drugs. Additionally, those skilled in the art will recognizeother useful shapes (e.g., threaded, oval, square, circle, etc.) forspecific applications (e.g., bone plug, plastic or cosmetic surgery,oviducts, etc.). Such constructs can be delivered through cannulas or bysyringe-like devices.

In another embodiment, shown in FIG. 11A, a hollow hemi-spherical device1100 depicts circumferentially aligned and compressed fibers 1110 andcorresponding inter fiber void space 1120. Methods of producing saidconstruct include compressing masses of fibrous dough-like materialaround spherical and hemi-spherical molds with and without rotation ofthe compression device and formation of bladders as previouslydescribed. FIG. 11B illustrates a cross section of a hollow device 1130that contains a material 1140. This material 1140 (e.g., cells,particulate, gel or fluid-like material, settable materials, etc.) mayhave been placed in the hollow device prior to or after implantation.Hollow structures as described above are useful for tissue engineeringapplications such as in-vivo cell reservoirs, drug delivery systems,plastic and reconstructive surgery implants, and shock absorbingindications as previously described. For example, bladders could beformed to receive autologous fat cells, which could be relocated withinthe body for cosmetic augmentation.

In another embodiment, a bladder manufactured by above methods may beused to reduce and repair a fractured vertebral body by inserting thebladder into the injury site and inflating (e.g., gel or fluid, settablefluid, etc.) to realign the spinal column by returning the vertebrasuperior and inferior of the injury site to their appropriate location.

In another embodiment, shown in FIG. 12A (top view) and FIG. 12 B (sideview), a ring of material 1200 is selectively compressed surrounding aminimally-compressed to non-compressed fibrous region 1210. The device1230 is useful in such applications such as a hernia patch or where asponge-like material is needed with the additional requirement ofsuturability around the periphery of the device. Similar to FIGS. 12Aand 12B, FIG. 13 depicts a device 1300 that contains a preferentiallycompressed region 1310 adjacent to a minimally-compressed tonon-compressed region 1320. Such a device may be useful in the repair oftransitional zones between tissues such as tendon to muscle or ligamentto bone.

It is believed that the high compressive forces will create chemicallinkages aside from the physical interaction of the fibers. In the caseof collagen, it is believed that the compressive force re-establishesnon-covalent forces such as hydrogen bonding, hydrophobic/hydrophilicinteractions, and electrostatic interactions, that the individual fibersand fibrils previously embodied in the native, pre-extracted tissues.These additional chemical linkages may act to create a pseudo-molecularweight increase to the matrix, providing improved mechanical propertiesprior to cross-linking, thereby providing for highly detailed crispmargins within the compressed fibrous construct that are locked in placewith cross-linking Constructs made using fibrous materials defined inthe prior art do not hold crisp margins. Therefore, material in thisembodiment would be useful as, but not limited to, devices for cosmeticand reconstructive surgery, intervertebral disks, joint meniscus andhollow tissues and organs (e.g., intestine, esophagus, ureter, etc.).

In another embodiment, a fibrous material can be compressed into a moldcontaining a structure or component (e.g., ring, mesh, particulate,screw, rod, etc.) to which the fibers attach, after which cross-linkingmay occur. The compressed fibers support, confine, and lock thestructure or component within a spatial conformation. Additionally, thestructure or construct may be porous and permit interdigitation of thefibers. This porosity also assists in the removal of fluid/lubricantduring compression. If desired, vacuum can be used to facilitate drawingof fluid and fibers into the porosity. The lubricant may itself functionas a bridging agent locking the fibrous coating to the porousreinforcing material.

Additionally, the compressed fibrous material may contain reinforcingmaterials such as long polymer threads or mesh(es) or may includeparticulates or biologically active agents. (e.g., growth factors,hormones, bmp, drugs, cells, viruses, etc.) Additionally, thebiologically active agents could be located within fibers making up thecompressed fibrous material, mechanically or chemically attached to thefibers making up the compressed material, between the fibers in theinter fiber void space, or suspended within a hydration fluid or secondsoluble polymer suspended in the inter fiber void space. Thebiologically active agents and/or soluble polymer may be added prior toor after fiber compression and prior to or after cross-linking.

In various embodiments, the fibrous matrix material may be composed oflayers of the same or different types of polymers. It is envisioned thatthis invention may be useful for medical devices that require specificabilities, material or mechanical properties, or biological conditionsto function optimally in the body. For example, devices may undergochanges in loading over time, require specific degradation rates, may beloaded differently across the surface of the implant, etc. Toaccommodate the special requirements of some devices, layers ofdifferent compressed fibrous matrix material may be layered with two ormore different polymers comprising one device. The layers of compressedfibrous material may increase or decrease degradation, providecontrolled drug delivery to specific locations, etc. The layers may bestacked on one another or side-by-side. The layers may be fused togetherand may be separated by layers of biologics, particulates, orreinforcing materials. The layers will provide the device the ability tobe multi-functional. For example, one or more layers will perform onefunction (e.g., provide structurally integrity, maintain shape, etc.)for the device while one or more other layers perform another function(e.g., drug delivery, allow tissue ingrowth). Another way to modify thedevice is by compressing the layers by different methods or by differentamounts of compression.

In another embodiment, two or more pre-compressed fibrous masses ofdough-like material may be layered and compressed to create a laminatedstructure. The fibrous mass may or may not consist of differentpolymers. Depending on the starting material composition and compressiveforces used, resultant constructs range in composition from a singlehomogeneous structure to a multi-layered laminate. Gradients and/orlaminates may also be created in a similar fashion by layering multiplesheets of varying compressions and composition before applying a finalcompression to laminate them into a single unit. In another embodiment,reinforcing materials, foamed polymer sheets, biologically activeagents, sheets of microstructure, particulates, etc. may be placedbetween the layers before compression. In another embodiment, apre-compressed sheet is roll-compressed, radially creating a spirallaminate suitable for controlled drug delivery and creation of nerveguides when wrapped around a removable central core material.

In another embodiment, compressed porous matrix material can be machinedor molded into distinctive geometric shapes useful as internal fixationdevices used for surgical repair, replacement, or reconstruction ofdamaged bone or soft tissue in any area of the body. Internal repairdevices may be successfully employed for many conditions, such asorthopedic, spinal, maxiofacial, craniofacial, etc. Compressed fibrousmatrix material can be machined or molded into any configuration. Invarious embodiments illustrated in FIGS. 14A and 14B, internal fixation,trauma, or sport medicine devices may be fabricated into anyconfiguration from the compressed fibrous matrix material. For example,the device 1400 shown in FIG. 14A is a T-shaped compressed fibrousconstruct intended for implantation into an osteoarthritic joint. Tab1410 separates the damaged joint surfaces and functions as a cushionwhile wings 1420 provide anchorage points to prevent migration of thedevice. Device 1430 shown in FIG. 14B is a Y-shaped compressed fibrousconstruct intended for repair and reinforcement of damaged ligaments andtendons. In a ligament application/procedure the damaged tissue isplaced in between tabs 1440 and secured in place with tacks, staples orsutures. Extension 1450 is then approximated to the original insertionpoint on the long bone and secured by methods such as interferencescrews, tacks or staples. Additional applications, such as anaugmentation device for the anterior cruciate ligament (ACL), forconstructs illustrated in FIGS. 14A and 14B or similar constructs willbe obvious to those skilled in the art.

One embodiment of the device can be used to aid in the repair of muscleand tendon surrounding a joint. In FIG. 15, a glenohumeral joint 1500 inwhich damaged tissue 1510 encompassing the rotator cuff is shown alongwith the device 1520. The rotator cuff is made up of the confluenttendons of four muscles (i.e. supraspinatus, infraspinatus,subscapularis, teres minor) originating on the scapula 1530, and is alsoassociated with tendon from the long end of the bicep. These musclescontrol the proximal end of the humerus 1540, which is inserted into theglenoid cavity of the scapula. The damage to the rotator cuff may be atear in one of the tendon insertions (for example a crescent or an acuteL-shaped tear of the supraspinatus). In this case, the invention can beused as a reinforcement patch. The tear is repaired by normal suturing,and is then protected and reinforced by overlaying the repair with theinvention. The muscle will be able to function, but while it is healing,the reinforcement patch takes on some of the load. Additionally, tissuewill become integrated within the pores of the overlay graft and theimplant will add bulk mass and strength to the repaired muscle tissue.In the situation where the torn muscle and tendon cannot be fixed bysuture alone, an alternate use for the invention is to act as anartificial tendon. In the example of a torn infraspinatus tendon, theinvention is sutured to a secure area of the torn infraspinatus. Theimplant material can then bridge the necessary distance and be suturedto the posterior aspect of the greater tuberosity of the humerus.

TABLE 1 Examples of Biodegradable Polymers for Construction of theFibrous Device Aliphatic polyesters Cellulose Chitin Collagen Copolymersof glycolide Copolymers of lactide Elastin Fibrin Glycolide/l-lactidecopolymers (PGA/PLLA) Glycolide/trimethylene carbonate copolymers(PGA/TMC) Hydrogel Lactide/tetramethylglycolide copolymersLactide/trimethylene carbonate copolymers Lactide/ε-caprolactonecopolymers Lactide/σ-valerolactone copolymers L-lactide/dl-lactidecopolymers Methyl methacrylate-N-vinyl pyrrolidone copolymers Modifiedproteins Nylon-2 PHBA/γ-hydroxyvalerate copolymers (PHBA/HVA)PLA/polyethylene oxide copolymers PLA-polyethylene oxide (PELA) Poly(amino acids) Poly (trimethylene carbonates) Poly hydroxyalkanoatepolymers (PHA) Poly(alklyene oxalates) Poly(butylene diglycolate)Poly(hydroxy butyrate) (PHB) Poly(n-vinyl pyrrolidone) Poly(orthoesters) Polyalkyl-2-cyanoacrylates Polyanhydrides PolycyanoacrylatesPolydepsipeptides Polydihydropyrans Poly-dl-lactide (PDLLA)Polyesteramides Polyesters of oxalic acid Polyglycolide (PGA)Polyiminocarbonates Polylactides (PLA) Poly-l-lactide (PLLA)Polyorthoesters Poly-p-dioxanone (PDO) Polypeptides PolyphosphazenesPolysaccharides Polyurethanes (PU) Polyvinyl alcohol (PVA) Poly-β-hydroxypropionate (PHPA) Poly-β-hydroxybutyrate (PBA)Poly-σ-valerolactone Poly-β-alkanoic acids Poly-β-malic acid (PMLA)Poly-ε-caprolactone (PCL) Pseudo-Poly(Amino Acids) Starch Trimethylenecarbonate (TMC) Tyrosine based polymers

TABLE 2 Examples of Biologically Active Agents Deliverable via thePresent Invention Adenovirus with or without genetic material AlcoholAmino Acids L-Arginine Angiogenic agents Angiotensin Converting EnzymeInhibitors (ACE inhibitors) Angiotensin II antagonists Anti-angiogenicagents Antiarrhythmics Anti-bacterial agents Antibiotics ErythromycinPenicillin Anti-coagulants Heparin Anti-growth factors Anti-inflammatoryagents Dexamethasone Aspirin Hydrocortisone Antioxidants Anti-plateletagents Forskolin GP IIb-IIIa inhibitors eptifibatide Anti-proliferationagents Rho Kinase Inhibitors(+)-trans-4-(1-aminoethyl)-1-(4-pyridylcarbamoyl) cyclohexaneAnti-rejection agents Rapamycin Anti-restenosis agents Adenosine A_(2A)receptor agonists Antisense Antispasm agents Lidocaine NitroglycerinNicarpidine Anti-thrombogenic agents Argatroban Fondaparinux Hirudin GPIIb/IIIa inhibitors Anti-viral drugs Arteriogenesis agents acidicfibroblast growth factor (aFGF) angiogenin angiotropin basic fibroblastgrowth factor (bFGF) Bone morphogenic proteins (BMP) epidermal growthfactor (EGF) fibrin granulocyte-macrophage colony stimulating factor(GM-CSF) hepatocyte growth factor (HGF) HIF-1 insulin growth factor-1(IGF-1) interleukin-8 (IL-8) MAC-1 nicotinamide platelet-derivedendothelial cell growth factor (PD-ECGF) platelet-derived growth factor(PDGF) transforming growth factors alpha & beta (TGF-.alpha., TGF-beta.)tumor necrosis factor alpha (TNF-.alpha.) vascular endothelial growthfactor (VEGF) vascular permeability factor (VPF) Bacteria Beta blockerBlood clotting factor Bone morphogenic proteins (BMP) Calcium channelblockers Carcinogens Cells and cellular material Adipose cells Bloodcells Bone marrow Cells with altered receptors or binding sitesEndothelial Cells Epithelial cells Fibroblasts Genetically altered cellsGlycoproteins Growth factors Lipids Liposomes Macrophages Mesenchymalstem cells Progenitor cells Reticulocytes Skeletal muscle cells Smoothmuscle cells Stem cells Vesicles Chemotherapeutic agents Ceramide TaxolCisplatin Cholesterol reducers Chondroitin Collagen Inhibitors Colonystimulating factors Coumadin Cytokines prostaglandins Dentin EtretinateGenetic material Glucosamine Glycosaminoglycans GP IIb/IIIa inhibitorsL-703, 081 Granulocyte-macrophage colony stimulating factor (GM-CSF)Growth factor antagonists or inhibitors Growth factors Bone morphogenicproteins (BMPs) Core binding factor A Endothelial Cell Growth Factor(ECGF) Epidermal growth factor (EGF) Fibroblast Growth Factors (FGF)Hepatocyte growth factor (HGF) Insulin-like Growth Factors (e.g. IGF-I)Nerve growth factor (NGF) Platelet Derived Growth Factor (PDGF)Recombinant NGF (rhNGF) Tissue necrosis factor (TNF) Transforming growthfactors alpha (TGF-alpha) Transforming growth factors beta (TGF-beta)Vascular Endothelial Growth Factor (VEGF) Vascular permeability factor(UPF) Acidic fibroblast growth factor (aFGF) Basic fibroblast growthfactor (bFGF) Epidermal growth factor (EGF) Hepatocyte growth factor(HGF) Insulin growth factor-1 (IGF-1) Platelet-derived endothelial cellgrowth factor (PD-ECGF) Tumor necrosis factor alpha (TNF-.alpha.) Growthhormones Heparin sulfate proteoglycan HMC-CoA reductase inhibitors(statins) Hormones Erythropoietin Immoxidal Immunosuppressant agentsInflammatory mediator Insulin Interleukins Interlukin-8 (IL-8)Interlukins Lipid lowering agents Lipo-proteins Low-molecular weightheparin Lymphocites Lysine MAC-1 Methylation inhibitors MorphogensNitric oxide (NO) Nucleotides Peptides Polyphenol PR39 ProteinsProstaglandins Proteoglycans Perlecan Radioactive materials Iodine - 125Iodine - 131 Iridium - 192 Palladium 103 Radio-pharmaceuticals SecondaryMessengers Ceramide Somatomedins Statins Stem Cells Steroids ThrombinThrombin inhibitor Thrombolytics Ticlid Tyrosine kinase Inhibitors ST638AG-17 Vasodilators Histamine Forskolin Nitroglycerin Vitamins E C YeastZiyphi fructus

The inclusion of groups and subgroups in Table 2 is exemplary and forconvenience only. The grouping does not indicate a preferred use orlimitation on use of any drug therein. That is, the groupings are forreference only and not meant to be limiting in any way (e.g., it isrecognized that the Taxol formulations are used for chemotherapeuticapplications as well as for anti-restenotic coatings). Additionally, thetable is not exhaustive, as many other drugs and drug groups arecontemplated for use in the current embodiments. There are naturallyoccurring and synthesized forms of many therapies, both existing andunder development, and the table is meant to include both forms.

TABLE 3 Examples of Reinforcing and/or Biologically Active ParticulatesAlginate Bioglass Calcium Compounds Calcium Phosphate Ceramics ChitosanCyanoacrylate Collagen Dacron Demineralized bone Elastin Fibrin GelatinGlass Gold Hyaluronic acid Hydrogels Hydroxy apatite Hydroxyethylmethacrylate Hyaluronic Acid Liposomes Mesenchymal cells NitinolOsteoblasts Oxidized regenerated cellulose Phosphate glassesPolyethylene glycol Polyester Polysaccharides Polyvinyl alcoholPlatelets, blood cells Radiopacifiers Salts Silicone Silk Steel (e.g.Stainless Steel) Synthetic polymers Thrombin Titanium

The following examples are given for purposes of illustration to aid inunderstanding the invention and it is to be understood that theinvention is not restricted to the particular conditions, proportion,and methods set forth therein.

Example 1

Starting with a dough-like material (90:10 ratio of fibrous collagen(Semed F, supplied by Kensey Nash Corporation) to soluble collagen(Semed S, supplied by Kensey Nash Corporation)) (approximately 20%solids), the composition was rolled into a flat sheet approximately 5 mmthick. This was then sandwiched between two sheets of wicking material,such as a paper towel. This entire arrangement was placed in a 30 tonhydraulic press at 60,000 lbf. The product was left until equilibriumwas achieved and no additional water was being expelled from the productat the given pressure. The press was opened and the product was removedas an approximately 1 mm sheet. An expansion of approximately 30-40% wasnoted in a radial direction. The sheet was cross-linked using 50 mM EDC(pH 5.4) in water. The sheet was soaked overnight in the solution andthen serially rinsed 3× for 2 hours with agitation in water. Tearstrengths in excess of 120 N were achieved.

Example 2

Starting with a fibrous dough-like material (90:10 ratio of fibrouscollagen (Semed F, supplied by Kensey Nash Corporation) to solublecollagen (Semed S, supplied by Kensey Nash Corporation)) (approximately20% solids), the composition was rolled into a flat sheet approximately5 mm thick. This was then sandwiched between two sheets of wickingmaterial, such as a paper towel. The product was then wrung through aset of high compression rollers allowing the wicking material to removea large portion of the available water. It was noted the materialexpanded in both the lengthwise and widthwise directions unlessconstrained in one direction. The sheet was then freeze dried topreserve the small amount of porosity that was still remaining withinthe sample.

Example 3

Starting with a fibrous dough-like material (85:15 ratio of fibrouscollagen (Semed F, supplied by Kensey Nash Corporation) to solublecollagen (Semed S, supplied by Kensey Nash Corporation)) (approximately12% solids), the composition was spread into a flat sheet approximately3 mm thick. This was then sandwiched between two sheets of wickingmaterial, such as a paper towel. The entire composition was then placedin a 30 ton hydraulic press and subjected to 60,000 lbf for 15 minutes.The sheet was removed and a thickness of approximately 0.2 mm was noted.Additionally, the material had expanded radially 200-300%. The materialwas crosslinked using 50 mM EDC (pH 5.4) in water. The sheet was soakedovernight in the solution and then serially rinsed 3× for 2 hours withagitation in water. This was then allowed to air dry.

Thus since the invention disclosed herein may be embodied in otherspecific forms without departing from the spirit or generalcharacteristics thereof, some of which forms have been indicated, theembodiments described herein are to be considered in all respectsillustrative and not restrictive, by applying current or futureknowledge. The scope of the invention is to be indicated by the appendedclaims, rather than by the foregoing description, and all changes whichcome within the meaning and range of equivalency of the claims areintended to be embraced therein.

1) The method of fabricating a fibrous member comprising the steps of:a) providing a mixture, said mixture comprising a plurality of fibers, alubricant, and a suspension fluid, said suspension fluid filling a voidspace between said fibers; b) subjecting said mixture to at least onecompressive force, said compressive force causing the migration and atleast partial alignment of said fibers; and c) removing substantiallyall of said suspension fluid from said mixture. 2) The method of claim1, wherein said mixture further comprises a biologically active agent.3) The method of claim 1, wherein said mixture further comprises areinforcing agent. 4) The method of claim 2, wherein said mixturefurther comprises a reinforcing agent. 5) The method of claim 1, whereinsaid removing of said suspension fluid comprises wicking away suspensionfluid that is on an exterior surface of said fibrous member. 6) Themethod of claim 2, wherein said wicking away of suspension fluidinvolves compressing said mixtures against at least one wicking element7) The method of claim 1, wherein said compressive forces reduce saidvoid space between said fibers. 8) The method of claim 1, wherein saidlubricant is in the form of a liquid. 9) The method of claim 1, whereinsaid lubricant is in the form of a solid. 10) The method of claim 9,wherein said solid lubricant is further provided in a carrier fluid. 11)The method of claim 1, wherein said compressive force induces flow ofthe suspension fluid. 12) The method of claim 11, wherein saidsuspension fluid flow causes plates of oriented fibers to be formed. 13)The method of claim 1, wherein said compressive force is applied by amolding surface, thereby creating a shaped fibrous member in said mold.14) The method of claim 13, wherein said shaped fibrous member is in theshape selected from the group comprising a sheet, cylinder, block,sphere, tube, and a valve. 15) The method of claim 1, further comprisingthe step of: d) machining said compressed mixture. 16) The method ofclaim 1, further comprising the step of: d) cross-linking at least aportion of said compressed mixture by exposure to a cross-linking agent.17) The method of claim 16, further comprising the step of: e) machiningsaid compressed mixture. 18) The method of claim 1, further comprisingthe step of: d) drying said compressed mixture. 19) The method of claim18 further comprising the step of: e) cross-linking at least a portionof said dried, compressed mixture by exposure to a cross-linking agent.20) The method of claim 19 further comprising the step of: f) machiningsaid compressed mixture. 21) The method of fabricating a fibrous membercomprising the steps of: a) providing a mixture, said mixture comprisinga plurality of fibers, a lubricant and a suspension fluid, saidsuspension fluid filling a void space between said fibers; b) subjectingsaid mixture to at least one compressive force, said compressive forcecausing the migration and at least partial alignment of said fibers; c)cross-linking at least a portion of said mixture; d) subjecting said atleast partially cross-linked mixture to a second compressive force; ande) removing substantially all of said suspension fluid from saidmixture.